DESCRIPTION: The proposed project has two main objectives: 1) to show that the pleiotropic cytokine leukemia inhibitory factor (LIF) administered via a recombinant adeno-associated virus (rAAV) vector centrally or peripherally, can control body weight (BW) gain for extended periods of time in normal lean rats, obese rats with specific genetic defects, and in diet-induced obese (DIO) leptin-resistant rats; and 2) to demonstrate that this effect is derived by affecting a change in intracellular downstream signal transduction pathways involving STAT-3 (signal transducer and activator of transcription) and SOCS-3 (suppressor of cytokine signaling) similar to those induced by the hormone leptin in hypothalamic neurons. Specifically, a series of recombinant adeno-associated virus (rAAV) vectors carrying human LIF cDNA under the control of a strong constitutive and inducible promoters will be constructed and tested in lean Sprague-Dawley (SD), obese Zucker fa/fa, as well as in DIO rodent rat models. Earlier the investigators have shown that a rAAV encoding 1) the lipostatic hormone leptin; and 2) the ciliary neurotrophic factor (CNTF) could be successfully used to maintain BW in lean and leptin-resistant obese fa/fa Zucker rats respectively. Likewise, they have demonstrated that a rAAV-hLIF is efficient to restrain the normal BW gain in SD rats when administered centrally. Here Dr. Zolotukhin and his colleagues propose to evaluate an anorexigenic effect of LIF using different routes of vector delivery in several lean and obese rat models concomitant with the analysis of activation of hypothalamic signal transduction pathways leading to the BW loss. The results of these studies will not only determine if gene therapy is a safe and viable long-term therapeutic strategy to control BW, but may also establish LIF as an effective leptin substitute in models of leptin resistance caused by environmental (DIO) or genetic factors and elucidate the impact on hypothalamic neurochemical signaling and associated metabolic disorders.